In humans, there is a sizable burden of inherited mutations that contributes to ill health throughout the world. This includes vast numbers of people with common hemoglobinopathies caused by a single gene alteration (sickle cell anemia, alpha- and beta-thalassemia) and genetic variants that contribute to the burden of "common" diseases present in all populations such as cardiovascular disease, cancer, and diabetes. The bulk of this morbidity and mortality arises from transmission of mutant genes from affected or carrier parents to their children. Some affected individuals also arise each generation as a result of inheriting a de novo germline mutation from unaffected parents. Although this is relatively rare, new germline mutations are the sole source of the heritable genetic variation that contributes not only to the "genetic load" of our species but also to the raw materials for adaptive evolution. Our proposal is focused on studying new mutations that occur in the human male germline using a new set of molecular tools to analyze sperm DNA. We plan to study two dominantly inherited conditions, achondroplasia, and Apert syndrome. Our goal is to help explain why the chance of a father having an affected child with a new mutation increases with his age and whether fathers of sporadic cases have the same susceptibility to mutation as men in the general population. In addition, we will test the hypothesis that germline stem cells heterozygous for one of these mutations may have a selective advantage over wild type cells thereby explaining the unexpectedly high mutation frequency typical of both conditions. Relevance: The illness and death due to human genetic disease results from the transmission of mutant genes from affected or carrier parents to their children and the inheritance each generation of new mutations. Our proposal is focused on studying the frequency of new mutations that occur in human sperm using a new set of molecular tools. We plan to study achondroplasia and Apert syndrome with the goal of understanding why the chance of a father transmitting a new mutation to his child increases with his age.